Dosage forms exhibiting multi-phasic release kinetics and methods of manufacture thereof

ABSTRACT

Dosage forms prepared by solid free form fabrication (SFF) provide release of medicament in multiple phases.

CROSS REFERENCE TO RELATED APPLICATION

[0001] This application is a continuation of pending U.S. patentapplication Ser. No. 09/027,290, filed Feb. 20, 1998, which is acontinuation in part of U.S. patent application Ser. No. 08/464,593filed Jun. 5, 1995, now U.S. Pat. No. 5,869,170, which is a divisionalapplication of U.S. patent application Ser. No. 08/138,345 filed on Oct.18, 1993, now U.S. Pat. No. 5,490,962.

TECHNICAL FIELD

[0002] The invention relates to methods of controlled drug delivery.More specifically the invention relates to dosage forms incorporatingone or more than one pharmaceutically active material.

BACKGROUND OF THE INVENTION

[0003] One of the problems with the current technology for drug deliveryis the lack of precision and resulting lack of quality control. This inturn causes a lack of precision in the release rates of the encapsulateddrug and requires that patients take the drug at specified timesthroughout the day. Oftentimes, especially for complex dosage regimes,patient compliance is well below acceptable levels, resulting indiminished therapeutic effect. Construction of drug delivery deviceswhich could release drugs according to complex prescribed temporalpatterns could have broad application for delivery of bioeffectingagents by both oral and implantable routes. For example, implants toareas of the body not easily accessed, such as the ocular cavity, can bedesigned for prolonged drug delivery. Dosage forms in which release ofactive coincides with circadian rhythms are also possible. In addition,patient compliance problems can be obviated by reducing the number oftimes a patient must self administer the drug.

[0004] U.S. Pat. No. 5,490,962 teaches the preparation of dosage formsusing solid free-form fabrication (SFF) methods. These methods can beadapted for use with a variety of different materials to create dosageforms with defined compositions, strengths, and densities, through theuse of computer aided design (CAD). Examples of SFF methods includestereo-lithography (SLA), selective laser sintering (SLS), ballisticparticle manufacturing (BPM), fusion deposition modeling (FDM), andthree dimensional printing (3DP) to precisely position bioactiveagent(s) within a release matrix to control the rate of release andallow either a pulsed or constant release profile.

[0005] The macrostructure and porosity of the dosage forms of the 'b 962patent can be manipulated by controlling printing parameters, the typeof polymer and particles size, as well as the solvent and/or binder.Porosity of the matrix walls, as well as the matrix per se, can bemanipulated using SFF methods, especially 3DP. Structural elements thatmaintain the integrity of the devices during erosion can also beincorporated so that more linear release of incorporated material isobtained. Most importantly, these features can be designed and tailoredusing computer aided design (CAD) for individual patients to optimizedrug therapy.

[0006] Despite the significant advances in drug delivery systems (DDS)described by U.S. Pat. No. 5,490,962, there is room for improvementimplementing 3DP to produce suitable dosage forms. For example, thetreatment of various disorders with multiple drug therapy may requiredifferent release rates for each drug. A single dosage form combiningthe multiple drugs would require separate domains for drug release atthe different rates. Drugs having high potency and/or toxicity requirespecial handling for both safety reasons and consistency in dose level.Other drugs may have low solubility in bodily fluids, requiring thatthey be modified for proper absorption. Certain drug therapies mayrequire pulsatile release over prolonged periods.

[0007] The present invention addresses these needs.

SUMMARY OF THE INVENTION

[0008] It is accordingly an aspect of the invention to provide amultiphasic dosage form capable of providing delivery of multiple drugshaving different release characteristics.

[0009] It is another aspect of the invention to provide a multiphasicdosage form, as above, which provides pulsatile release for one drug andcontinuous release for another drug.

[0010] It is yet another aspect of the invention to provide amultiphasic dosage form incorporating a small, precisely measured amountof a high potency and/or high toxicity drug.

[0011] It is yet another aspect of the invention to provide amultiphasic dosage form which provides adequate absorption of a drugwhich is sparingly soluble in bodily fluid.

[0012] It is another aspect of the invention to provide a method formaking the above dosage forms.

[0013] These objects and others set forth more fully hereinabove, areachieved by a method for forming a multiphasic dosage form containingone or more than one pharmaceutically active material. The methodcomprises the steps of (a) preparing a first layer of pharmaceuticallyacceptable particulates on a platform; (b) forming a first pattern ofadhered particulates in the first layer by applying a binder to selectedportions of the first layer, the first pattern incorporating one of thepharmaceutically acceptable particulates over the first layer; (d)forming a second pattern of adhered particulates which is the same ordifferent from the first pattern, by applying a binder to selectedportions of the second pattern incorporating a second pharmaceuticallyactive material and being adhered to the first pattern along aninterface thereof to thereby produce a three dimensional dosage form.

BRIEF DESCRIPTION OF THE DRAWINGS

[0014] For a full understanding of the invention, the following detaileddescription should be read in conjunction with the drawings, wherein:

[0015]FIG. 1 is a schematic drawing of one embodiment of the process ofthe invention;

[0016]FIG. 2(a) is one embodiment of a microdose dosage form of theinvention;

[0017]FIG. 2(b) is another embodiment of a microdose dosage form; and

[0018]FIG. 2(c) is a dosage form of the invention showing totalencapsulation.

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0019] Solid free-form fabrication methods offer several uniqueopportunities for the construction of dosage forms. These dosage formscan be constructed with a specified drug composition gradient andstructure so that the dosage regimes can be much more complex thancurrently practiced and tailored for the needs of individual patients.SFF methods can be used to selectively control composition within thebuild plane by varying the composition of printed material. This meansthat unconventional microstructures, such as those with complicatedporous networks or unusual composition gradients, can be designed at aCAD terminal and built through an SFF process such as 3DP.

[0020] Three dimensional printing is described by Sachs et al.,“CAD-Casting: Direct Fabrication of Ceramic Shells and Cores by ThreeDimensional Printing,” Manufacturing Review 5(2):117-126 (1992) and U.S.Pat. No. 5,204,055, the teachings of which are incorporated herein.Suitable devices include both those with a continuous jet stream printhead and a drop-on-demand (DOD) print head. A continuous jet headprovides for a fluid that is pressure driven through a small orifice.Droplets naturally break off at a frequency that is a function of thefluids properties and the orifice diameter. Initial prototype dosageforms were built using a single jet head. Multiple jet heads arepreferred.

[0021] A DOD printhead utilizes individual solenoid valves that run atfrequencies up to 1.2 kHz. Fluid is also pressure driven through thesevalves and a small orifice is downstream of the valves to ensureaccurate and repeatable droplet size.

[0022] Both raster and vector apparatuses can be used. When using DOD araster apparatus provides that the printhead goes back and forth acrossthe bed with the jet turning on and off. A continuous jet is always on,and a vector apparatus is used similar to an x-y printer.

[0023] 3DP is used to create a solid object by ink-jet printing a binderonto selected areas of sequentially deposited layers of powder orparticulates. In the following description, the terms “powder” and“particulates” are used interchangeably. Each layer is created byspreading a thin layer of powder over the surface of a powder bed. In apreferred embodiment, a moveable powder piston is located within acylinder, with a powered roller to deliver dispensed powder to areceiving platform located adjacent to the powder feeder mechanism.Operation consists of raising the feed piston a determined amount foreach increment of powder delivery. The roller then sweeps across thesurface of the powder feeder cylinder and deposits it as a thin layeracross the receiving platform immediately adjacent to the powder feeder.The powder feeding piston is then lowered as the roller is brought backto the home position, to prevent any back delivery of powder.

[0024] The powder piston and cylinder arrangement can also consist ofmultiple piston/cylinders located in a common housing, which would beused to dispense multiple powders in the following sequence:

[0025] 1. Line up the first desired powder cylinder with therolling/delivery mechanism

[0026] 2. Increment the movable position piston up to deliver anincremental amount of powder

[0027] 3. Activate roller to move powder to receiving platform

[0028] 4. Lower the powder piston driving mechanism

[0029] 5. Laterally slide the powder feeder housing such that the nextdesired powder cylinder is lined up with the delivery mechanism

[0030] 6. Repeat steps 2, 3, 4 and 5

[0031] 7. Continue for as many different powders and/or powder layers asrequired.

[0032] This method of powder feeding can be controlled manually or befully automated. Cross contamination of different powders is minimizedsince each powder is contained in its own separate cylinder. One of theadvantages to this method is that only one piston raising/loweringmechanism is required for operation, regardless of the number of powdercylinders. By raising the powder for delivery rather than dropping itfrom above, problems associated with gravity based delivery systems suchas “ratholing,” incomplete feed screw filling/emptying and “dusting”with the use of fine powders is eliminated or minimized since onlyenough energy is introduced to move the powder up an incremental amount.The powder feeder housing, with its multiple cylinders and pistons, canalso be designed as a removable assembly, which would minimizechangeover times from one powder system to another.

[0033] The powder bed is supported by a piston which descends uponpowder spreading and printing of each layer (or, conversely, the inkjets and spreader are raised after printing of each layer and the bedremains stationary). Instructions for each layer are derived directlyfrom a computer-aided design (CAD) representation of this component. Thearea to be printed is obtained by computing the area of intersectionbetween the desired plane and the CAD representation of the object. Theindividual sliced segments or layers are jointed to form the threedimensional structure. The unbound powder supports temporarilyunconnected portions of the component as the structure is built but isremoved after completion of printing.

[0034] The 3DP process is shown schematically in FIG. 1, wherein a 3DPapparatus is indicated generally by the number 10. Powder 12 is rolledfrom a feeder source (not shown) in stage 1 with a powder spreader 14onto a surface 16 of a build bed 18. The thickness of the spread layeris varied as a function of the type of dosage form being produced.Generally the thickness of the layer can vary from about 100 to about200 μm. The printhead 22 then deposits the binder (fluid) 24 onto thepowder layer and the build piston 26 is lowered one layer distance.Powder is again rolled onto the build bed 18 and the process is repeateduntil the dosage forms are completed (stages 2 and 3 of FIG. 1). Thedroplet size of the fluid is from about 50 to about 500 μm in diameter.Servo motors (not shown) are used to drive the various actions of theapparatus 10.

[0035] While the layers become hardened or at least partially hardenedas each of the layers is laid down, once the desired final partconfiguration is achieved and the layering process is complete, in someapplications it may be desirable that the form and its contents beheated or cured at a suitably selected temperature to further promotebinding of the powder particles. In either case, whether or not furthercuring is required, the loose unbonded powder particles are removedusing a suitable technique, such as ultrasonic cleaning, to leave afinished device.

[0036] As an alternative to ultrasonic cleaning, water solubleparticulates may be used. Fabrication of structures with designed porestructures is a challenging task even with additive manufacturingprocesses such as 3DP. Cylindrical structures with radial pores ofhundreds of microns in diameter can be fabricated, however, the removalof loose powder from the narrow channels requires a cumbersome manualclean up process. One solution is to employ mixtures of water solubleparticulates (sodium chloride) with polymers used to fabricatespecimens. The small particles then leach out to reveal aninterconnected porous structure. While this technique is useful infabricating a network of pores, control of pore architecture is lost. Animprovement on this technique is to selectively deposit the solublephase to form internal soluble patterns prior to building any externalfeatures. Water soluble materials such as poly(ethylene glycol) can bedeposited on a flat surface prior to spreading a new layer of powder.This enables the process to build walls of soluble material. Loosepowder can be spread after completion of the patterning. The external orinsoluble features of the specimen can then be built by printing withbinder solution. Following the requisite iterations of the patterningand printing processes, produces a dosage form that has intricateinternal features that can be dissolved easily when immersed in anappropriate solvent. This concept can be used to fabricate componentswith controlled internal pore channels. These soluble patterns can alsobe used to create drug delivery devices with prescriptive release.Devices that are relatively insoluble in physiological fluids can bedesigned and fabricated with controlled soluble channels within. Uponingestion or implantation, dissolution of the channels will expose theactive that are isolated until the removal of the soluble phase in thechannels.

[0037] Construction of a 3DP component can be viewed as the knittingtogether of structural elements that result from printing individualbinder droplets into a powder bed. These elements are calledmicrostructural primitives. The dimensions of the primitives determinethe length scale over which the microstructure can be changed. Thus, thesmallest region over which the concentration of bioactive agent can bevaried has dimensions near that of individual droplet primitives.Droplet primitives have dimensions that are very similar to the width ofline primitives formed by consecutive printing of droplets along asingle line in the powder bed. The dimension of the line primitivedepend on the powder and the amount of binder printed per unit linelength. A line primitive of 500 μm width is produced if an ink jetdepositing 1.1 cc/min of methylene chloride is made to travel at 8″/secover the surface of a polycaprolactone (PCL) powder bed with 45-75 μmparticle size. Higher print head velocities and smaller particle sizesproduce finer lines. The dimensions of the primitive seem to scale withthat calculated on the assumption that the liquid binder or solventneeds to fill the pores of the region in the powder which forms theprimitive.

[0038] Finer feature size is also achieved by printing polymer solutionsrather than pure solvents. For example, a 10 wt. % PCL solution inchloroform produces 200 μm lines under the same conditions as above. Thehigher solution viscosity slows the migration of solvent away from thecenter of the primitive.

[0039] The solvent drying rate is an important variable in theproduction of polymer parts by 3DP. Very rapid drying of the solventtends to cause warping of the printed component. Much, if not all, ofthe warping can be eliminated by choosing a solvent with a low vaporpressure. Thus, PCL parts prepared by printing chloroform have nearlyundetectable amounts of warpage, while large parts made with methylenechloride exhibit significant warpage. It has been found that it is oftenconvenient to combine solvents to achieve minimal warping and adequatebonding between the particles. Thus, an aggressive solvent can be mixedin small proportions with a solvent with lower vapor pressure.

[0040] There are two principal methods for incorporation of bioactiveagent (e.g., a drug). In the first method, a layer of dispersed finepolymer powder is selectively bound by ink-jet printing a solvent ontothe polymer particles which dissolves the polymer. This process isrepeated for subsequent layers to build up the cylinder, printingdirectly on top of the preceding layer, until the desired shape isachieved. If it is desired to design a constant rate release matrix, thedrug is dissolved or dispersed (e.g., micellar) in the solvent, yieldingdrug dispersed evenly through the matrix. The printing process for thiscase would then be continued layer by layer until the desired shape wasobtained.

[0041] In the second method, devices for pulsed release of drugs areprepared by constructing drug-rich regions within the polymer matrix. Inthis case, multiple printheads are used to deposit drug containingsolvent in selected regions of the powder bed. The remaining volume ofthe desired device is bound with pure solvent deposited by a separateprinthead. The printing process is repeated layer by layer to yield adevice which gives a pulsed release of drug. For example, a cylindricaldevice could contain a cylindrical annulus region which is enriched witha drug.

[0042] Significant amounts of matter can be deposited in selectedregions of a component on a 100 μm scale by printing solid dispersionsor solid precursors through the ink-jet print heads with hundreds ofjets can be incorporated into the process. The large number ofindividually controlled jets make high rate 3DP construction possible.

[0043] A specific embodiment of the invention, the dosage form canincorporate a solubility or stability enhancer. Suitable materials inthis regard are cyclodextrins, cyclodextrin derivatives and/orsubstances that spontaneously forms micelles as solubility/stabilityenhancers to facilitate the dispensing procedure, as well as thereleasing pattern of poorly/sparingly soluble or unstable drugs in thefabrication of 3DP drug delivery systems (i.e., tablets, implants,etc.). Cyclodextrins (CDs) and their derivatives are commonly usedcomplexing agents (CA). When incorporated in the fabrication of 3DPdosage forms, CDs can be used as follows:

[0044] 1. to prepare aqueous solutions of sparingly soluble drugs sothey can be dispensed in sufficient concentration through the nozzle,thus avoiding the use of suspensions and minimizing the need forextensive solvent removal or drying;

[0045] 2. to increase drug stability by preventing labilegroups/molecules from interacting with solvent;

[0046] 3. to form a drug complex in situ, so that wetting andsolubilization are enhanced when in contact with GIT fluids (oral DDS)or subcutaneous fluids (implantable DDS). This substantially improvesthe rate of delivery leading to a desirable fast onset of therapeuticactivity, and,

[0047] 4. as a corollary of 3. above, when CA is placed at the bottom ofa reservoir (designed within the dosage form) it will act as a carrierthat facilitates/assists the release of remaining drug, which in turnleads to the desired fast offset of activity and prevents undesirableleaching out of sub-therapeutic drug levels.

[0048] By properly combining 3 and 4 above, a desirable pulsing patterncan be achieved.

[0049] By combining the properties of drug-complex systems with the 3DPfabrication process the three scenarios and any combination/variation ofthem can be produced/modeled to provide a solution to a particular drugrelease profile to be achieved.

[0050] Surface finish of the dosage forms of the invention is governedby the physical characteristics of the materials used as well as thebuild parameters. These factors include particle size, powder packing,surface characteristics of the particles and printed binder (i.e.,contact angle), exit velocity of the binder jet, binder saturation,layer height, and line spacing. Interaction of the binder liquid withthe powder surface, in particular, can be controlled carefully tominimize surface roughness. In a case where the binder bets wicked outin a large area, the feature size control becomes difficult, resultingin a rough surface.

[0051] In one embodiment, the invention circumvents this problem incases where no substitute material combinations can be found. Anintermediary material can be deposited on a powder bed to form a wettingbarrier for the binder material. These intermediaries are deposited insuch as fashion that spreading of the subsequently printed binder ishindered by the presence of the “outlining” intermediary region. Anextreme example will be the printing of an oil around the specimen tolimit wicking of a water-based binder.

[0052] A number of materials are commonly used to form a matrix forbioactive agent delivery. Unless otherwise specified, the term “polymer”will be used to include any of the materials used to form the bioactiveagent matrix, including polymers and monomers which can be polymerizedor adhered to form an integral unit. In a preferred embodiment, theparticles are formed of a polymer, such as a synthetic thermoplasticpolymer, for example, ethylene vinyl acetate, poly(anhydrides),polyorthoesters, polymers of lactic acid and glycolic acid and other αhydroxy acids, and polyphosphazenes, a protein polymer, for example,albumin or collagen, or a polysaccharide containing sugar units such aslactose. The polymer can be non-biodegradable or biodegradable,typically via hydrolysis or enzymatic cleavage. Non-polymeric materialscan also be used to form the matrix and are included within the term“polymer” unless otherwise specified. Examples include organic andinorganic materials, such as hydoxyapatite, calcium carbonate, bufferingagents, and lactose, as well as other common excipients used in drugs,which are solidified by application of adhesive rather than solvent.

[0053] Erodible bioactive agent delivery devices are one of the simplestmedical devices that can be constructed. These types of bioactive agentdelivery devices can be used in an oral or implantable form depending onthe desired method for delivering the specific bioactive agent. Theydiffer in the time period over which the bioactive agent is deliveredand excipients used in the device construction. Erodible bioactive agentdelivery systems are constructed by dispersing the desired bioactiveagent in a matrix chosen so that it dissolves or decomposes in thepresence of a body fluid. Oral erodible systems, for example, begin todissolve when they contact with body fluid. In principle, release of thebioactive agent in both cases is controlled both by the rate at whichthe excipient reacts with the fluid and the rate of bioactive agentdiffusion out of the device. This is true only if the surface of thedevice erodes in a uniform manner and its internal structure remainsunchanged by prior reaction at the surface.

[0054] Photopolymerizable, biocompatible water-soluble polymers includepolyethylene glycol tetraacrylate (MW 18,500) which can bephotopolymerized with an argon laser under biologically compatibleconditions using an imitation such as triethanolamine,N-vinylpyrollidone, and eosin Y. Similar photopolymerizable macromershaving a poly(ethylene glycol) central block, extended with hydrolyzableoligomers such as oligo(d,l-lactic acid) or oligo (glycolic acid) andterminated with acrylate groups, may be used.

[0055] Examples of biocompatible polymers with low melting temperaturesinclude polyethyleneglycol 400 which melts at 4° C.-8° C., PEG 600 meltsat 20° C.-25° C., 1500 which melts at 44° C.-48° C., and stearic acidwhich melts at 70° C. Other suitable polymers can be obtained byreference to The Polymer Handbook, 3rd edition (Wiley, N.Y. 1989), theteachings of which are incorporated herein. The material forconstruction of the devices is selected based on the mechanism of drugtransport and compatibility of their processing technology with thestability of the bioactive agent.

[0056] The binder can be a solvent for the polymer and/or bioactiveagent or an adhesive which binds the polymer particles. Solvents formost of the thermoplastic polymers are known, for example, methylenechloride or other organic solvents. Organic and aqueous solvents for theprotein and polysaccharide polymers are also known, although an aqueoussolution is preferred if denaturation of the protein is to be avoided.In some cases, however, binding is best achieved by denaturation of theprotein.

[0057] The binder can be the same material as is used in conventionalpowder processing methods or may be designed to ultimately yield thesame binder through chemical or physical changes that take place in thepowder bed after printing, for example, as a result of heating,photopolymerization, or catalysis.

[0058] The selection of the solvent for the bioactive agent depends onthe desired mode of release. In the case of an erodible device, thesolvent is selected to either dissolve the matrix or is selected tocontain a second polymer which is deposited along with the drug. In thefirst case, the printed droplet locally dissolves the polymer powder andbegins to evaporate. The drug is effectively deposited in the polymerpowder after evaporation since the dissolved polymer is deposited alongwith the drug. The case where both the drug and a polymer are dissolvedin the printed solution is useful in cases where the powder layer is notsoluble in the solvent. In this case, binding is achieved by depositionof the drug polymer composite at the necks between the powder particlesso that they are effectively bound together.

[0059] Aggressive solvents tend to nearly dissolve the particles andreprecipitate dense polymer upon drying. The time for drying isprimarily determined by the vapor pressure of the solvent. There is arange from one extreme over which the polymer is very soluble, forexample, 30 weight percent solubility, which allows the polymer todissolved very quickly during the time required to print one layer, ascompared with lower solubilities. The degree to which the particles areattacked depends on the particle size and the solubility of the polymerin the solvent. Fine powder is more completely dissolved than powderwith larger particles size.

[0060] There are essentially no limitations on the bioactive agents thatcan be incorporated into the devices, although those materials which canbe processed into particles using spray drying, atomization, grinding,or other standard methodology, or those materials which can be formedinto emulsifications, microparticles, liposomes, or other smallparticles, and which remain stable chemically and retain biologicalactivity in a polymeric matrix, are preferred.

[0061] Those bioactive agents which can be directly dissolved in abiocompatible solvent are highly preferred. Bioactive agents alsoinclude compounds having principally a structural role, for example,hydroxyapatite crystals in a matrix for bone regeneration. The particlesmay have a size of greater than or less than the particle size or thepolymer particles used to make the matrix.

[0062] Examples generally include proteins and peptides,polysaccharides, nucleic acids, lipids, and non-protein organic andinorganic compounds, referred to herein as “bioactive agents” unlessspecifically stated otherwise. These materials have biological effectsincluding, but not limited to, anti-inflammatories, antimicrobials,anti-cancer, antivirals, hormones, antioxidants, channel blockers,growth factor, cytokines, lymphokines, and vaccines. It is also possibleto incorporate materials not exerting a biological effect such as air,radiopaque materials such as barium, or other imaging agents.

EXAMPLE 1 Intraocular Device Capable of Delivering an Anti-inflammatoryand Antiproliferative Drug

[0063] Anti-proliferative and anti-inflammatory agents are used to treata number of ocular diseases, including traction retinal detachment, thatoften result in blindness. Traction retinal detachment can develop inproliferative retinal diseases, such as proliferative diabeticretinopathy or after penetrating ocular trauma. The anti-proliferative,5-fluorouracil (5-FU), and the anti-inflammatory, diclofenac at aconstant rate from the same device. The dosage form has its applicationin the treatment of the proliferation and inflammation resulting fromtraction retinal detachment, especially after trauma.

[0064] Anti-proliferatives like 5-FU can be extremely toxic; in suchcases, pulsed intraocular deliver could produce the same therapeuticbenefits as continuous release while reducing side effects, toxicity innormal cells, and the risk of multiple drug resistance (MDR) in fibrouscells, thereby enhancing the efficacy of the treatment. Diclofenac, onthe other hand, is less toxic and is effective when delivered at aconstant rate.

[0065] The first step of the procedure is to optimize prescriptiverelease rates of 5-FU and diclofenac independently and thereaftercombine the two substructures into one device. The latter process isaccomplished by 3DP fabrication during a single manufacturing process.

[0066] Methods and Results

[0067] The implant can be divided into two portions. The top portionconsists of the 5-FU chambers and the lid layers that encapsulate theactives. These caps are designed to degrade at different rates to causethe drug to release at predetermined lag times. The lower portion of theimplant releases diclofenac at zero-order kinetics throughout thetherapy. Different portions of the intravitreal implant mandate distinctcharacteristics that cannot be achieved from a monolithic structure.Internal structure and composition at each portion of the implant deviceare controlled individually to meet the release characteristicscriteria.

[0068] Polymeric film degradation experiments are conducted to quicklyidentify candidate materials for constructing the intraocular implantdevices. The initial polymer selection is limited to products that areapproved by the United States FDA for use in humans. In addition, someof these polymers, such as polyanhydrides, are not widely availablecommercially. The polymers tested are further limited to thosecommercially available and those that could be prepared in powder form,however, other products may have characteristics which are suitable insome but not all of these criteria and are included within the scope ofthe present invention.

[0069] Different copolymers of the polyactides and polyglycolides of awide range of molecular weights are studied. These includepolyactide-co-glycolide (PLGA) with varying lactide: glycolide ratio(75:25, 50:50) and molecular weights ranging from 15 KDa to 60 KDa.Among the low molecular weight polylactides tested are poly (l-lactide)2 KDa. A number of different polyanhydrides are also evaluated for fasteroding lids. These include polysebacic acid (PSA), polyfatty aciddimer-sebacic acid (PFAD:SA; 50:50, 51 KDa), polyricinoleic acidmaleate-sebacic acid (PRAM: SA, 50:50, 34 KDa).

[0070] PLGA is chosen to form the slow eroding walls of the implantbased on the film degradation study. Polyanhydrides, especiallyP(FAD:SA) exhibit fast erosion characteristics. This makes P(FAD:SA) anideal system to be used in construction of the 5-FU caps. The surfaceerosion mechanism of polyanhydrides also suggests that differentthickness films can be used to control the lag time.

[0071] Pulsatile Release Implants

[0072] A number of prototype intraocular implant devices are fabricatedby 3DP. One implant has four chambers containing 5-FU. Walls of theimplant are fabricated by printing chloroform into thinly spread PLGApowders. Only the printed region became dense while the PLGA powder fromthe unprinted region remains unbound. A scanning electron micrograph(SEM) taken from the center of the device is used to confirm that themicrostructures desired, formation of four distinct compartments, during3DP fabrication process are achieved.

[0073] Two orthogonal walls form the separation between the fourchambers of the implant devices fabricated. Two different devices areconstructed by printing 8 lines side by side in one and 4 lines side byside in the other. Visible evidence from scanning electron micrographsdemonstrates that resulting wall thickness increases as the number ofprinting lines increases. Differences in the release characteristicsfrom these implant devices are also a function of printing line numberand therefore wall thicknesses.

[0074] Prototype implant devices are manually loaded with 160 μg 5-FUand polymeric caps are constructed on top of the chambers to encapsulatethe active agent. P(FAD:SA) powders are used to build caps of differentthicknesses. The PLGA walls are saturated with chloroform to enhancebonding to the P(FAD:SA) layer. Prototype implant devices that arefabricated with the presaturation steps do not exhibit any immediatedose dumping. Another design feature implemented to avoid prematuredumping of 5FU is an increase in the side wall thickness. This featureserved a dual purpose. The increased wall thickness effectivelydecreases the chance of 5-FU permeation through the side walls. At thesame time, the contact surface area between the side walls of thechamber and the top lid is increased, thus minimizing 5-FU release fromthe PLGA and P(FAD:SA) interface.

[0075] Drug release is analyzed by immersing the dosage in 10 ml ofphosphate buffered saline (PBS) solution kept at 37° C. Samples aretaken at predetermined intervals (at least 5 per assay) and analyzedusing quantitative HPLC. Approximately 90% of the drug is released,approximately 146 μg in separate bursts. A number of different prototypeimplant device designs are tested and yield distinctively differentrelease characteristics.

[0076] The release profile from four sets of different prototype designsare measured using an HPLC method. The first profile labeled asPrototype 3 is taken from implant devices with porous and looselyattached P(FAD:SA) lid layers. These implants showed complete 5-FUrelease within the first 24 hours of the study. This demonstrates thatthe 5-FU in the implant devices will pulse out rapidly from themicrochambers when there are enough pores to allow channeling of therelease medium. Modifications made in the processing conditions forPrototype 4 result in pore-free lid layers as was discussed earlier. Therelease profile of Prototype 4 shows a significant difference from thatof Prototype 3. A short lag time of ˜6 hours with peak release at 14hours is observed with Prototype 4 devices. These implant devicesexhibit imperfections at the PLGA and P(FAD:SA) interface to which couldbe attributed the relatively quick release of 5-FU. Further improvementsin the fabrication sequence and increased side wall thickness resultedin improved bonding between the PLGA walls and the P(FAD:SA) lid layers.Release profiles of Prototype 5 clearly demonstrated lag times of 24hours or 36 hours, depending on the number of lid layers. The number ofP(FAD:SA) lid layers also affect the release rates. A peak release rateof 5 μg per hour is achieved at 43 hours for the implants with 2 lidlayers while implants with 3 lid layers reach a peak of 2.5 μg per hourin 56 hours.

[0077] These data demonstrate that modifications in process parametersand implant design may be used to achieve pulsatile release of drugsfrom implants. Close examination of the pulses from the prototypeimplants suggest that once the implant configuration and material systemis optimized, multiple pulses from a single implant may be achieved.

[0078] In addition to the material systems investigated, other materialsystems that would erode faster without allowing significant diffusioncan be used for achieving pulsatile release. A further embodiment of thepresent invention is a device in which the device design is modified inorder to allow sequential exposure of the lid layers. In the proposedconfiguration, sequential inner 5-FU chambers are exposed to the releasemedium and only when the contents from the first chamber are exhausted.

[0079] Continuous Release Implants

[0080] Before fabrication of implant devices can be achieved, theoptimal 3DP parameters are determined. Polyesters are used as thepolymer phase, which are soluble in chloroform. Diclofenac is insolublein chloroform but readily soluble in methanol. The solubility ofdiclofenac in different ratios of methanol and chloroform isinvestigated in order to optimize the balance of high drug concentrationand polymer dissolution ability of the binder solution. In addition, theability of these solvent combinations to dissolve polyesters isexamined. It is determined that a 20:80 mixture of methanol:chloroformis optimal for dissolving the polymer while delivering a highconcentration of drug to the device. A homogeneous implant is achievedby incorporating 24 mg/ml of diclofenac into the binder solution, whichis deposited on a bed of polyester polymer.

[0081] Several diclofenac-containing prototypes are successfullyfabricated using the 3DP technology and tested for drug release instatic phosphate buffered saline solution at 37° C. An HPLC assay isdeveloped and tested for linearity, precision, specificity, andsensitivity prior to quantitative analysis of diclofenac.

[0082] a. Diclofenac Prototype 1

[0083] Six disks from the first prototype batch are exposed to liquidCO₂, to remove residual chloroform and determine if this process affectsthe diclofenac content. However, the amount of diclofenac in the disksexposed to liquid CO₂ is 7.2±0.2 mg (n=3), which is the same as disksexposed to liquid CO₂ s 1.9±0.3% (n=3), compared to 5.5±0.3% (n=3) forcontrol devices not exposed to liquid CO₂. Thus, exposure to liquid CO₂under these conditions reduces the amount of chloroform by 65% but doesnot affect diclofenac content.

[0084] These disks are homogenous with diclofenac distributed throughoutthe entire disk. The actual implant will contain an additional portionfor the pulsatile release of separate drug (i.e., 5-FU), thus, only onemajor face of the diclofenac section will be directly exposed to theexternal environment. As a result, subsequent prototypes contain aplacebo section to mimic the pulsatile section of the final implantdevice.

[0085] b. Diclofenac Prototype 2

[0086] Initial prototypes of the diclofenac intravitreal implant exhibithigh rate of release for 2 days (0.8 and 0.6 mg per day on days 1 and 2,respectively) which is attributable to the large, drug containingsurface area of the implant exposed to the dissolution medium.Thereafter, diclofenac release is continuous at measurable butsub-therapeutic rates (greater than 0.8 but less than 0.36 mg per day)for an additional 14 days.

[0087] c. Diclofenac Prototype 3

[0088] The second generation of prototypes is fabricated with a largefraction of the diclofenac-containing component capped with placebopolymer layers of different thickness. This results in an initial drugrelease that tapers and then gradually exceeds the target rate of 80 ugper day after 10 days. Furthermore, complete drug release was notobserved within the desired sixteen days.

[0089] d. Diclofenac Prototype 4

[0090] This batch is similar to Prototype 3 except that the placebo capis fabricated with 30% sodium chloride to create holes in the cap toincrease the initial release of diclofenac. This technique increasesdiclofenac release during the first day, but for the next 13 days, therelease rate is low, similar to Prototype 3.

[0091] e. Diclofenac Prototype 5

[0092] The previous prototypes exhibit drug release rates that vary fromhigh to low release or low to high release. To achieve zero-orderrelease, the interconnectivity of the diclofenac particles in thepolymer phase is increased without altering the drug loading by usingsodium chloride as an inert filler. Thus, prototype 5 disks arefabricated with a blend of PLGA polymer with sodium chloride. Theaddition of 35% (w/w) sodium chloride ensures that the combined loadingof diclofenac and sodium chloride is above the minimum necessary tocreate interconnected particles. A void volume or drug occupancy of 35%is recognized as above the minimum necessary to establish completeinterconnection of all pores and channels within a porous structure andis well known by those skilled in the art as “percolation theory.” Theseprototypes are also covered with a placebo polymer coating to inhibitinitial dose dumping by the implant. The results of this study indicatethat Prototype 5b exhibits the target diclofenac release range of 80μg/day.

[0093] f. Solvent Extraction

[0094] Preliminary experiments on post-fabrication exposure of thediclofenac prototypes to liquid CO₂ for 5, 30 and 60 minutes indicatethat the procedure reduces the amount of residual solvent in the implantdevices without significantly affecting diclofenac content. The resultsare summarized in Table 1. TABLE 1 EFFECT OF LIQUID CO2 EXPOSURE TIME ONDICLOFENAC CONTENT IN DEVICES MANUFACTURED BY 3DP USINGPOLYLACTIDE-CO-GLYCOLIDE AS THE POLYMER AND CHLOROFORM AS THE BINDERControl Residual CO₂ Exposure Diclofenac Diclofenac Chloroform Prototype# (min) (mg) (mg) (wt %) 1 5 7.30 7.3 ± 0.2 2.19 1 5 7.36 7.3 ± 0.2 1.671 5 7.07 7.3 ± 0.2 1.83 3 30 1.014 1.23 ± 0.02 0.35 3 60 1.038 1.23 ±0.02 0.39 3 60 1.007 1.23 ± 0.02 0.17 4 30 0.994 1.02 ± 0.09 0.12 4 600.995 1.02 ± 0.09 0.18

[0095] These results demonstrate that the fabrication of an implantabledevice or oral dosing device using 3DP can be manipulated to produce asingle device exhibiting both pulsatile and continuous active releaseover periods as long as days or weeks.

EXAMPLE 2 Contraceptive Implant Containing 17-DAN

[0096] A contraceptive implant device was designed for cyclic release of17-diacetylnorgestimate (17-DAN). Biodegradable polyesters of differenttypes and molecular weights including poly-l-lactic acid (PLLA) andpoly-epsilon-caprolactone (PCL) are used to construct different regionsof prototype devices in a single contiguous process. The regions formedincluded a slow-degrading outer framework as a drug release restraint, adrug-carrying core, and a diffusion layer for drug delivery ratecontrol. The drug is incorporated in the implant core surrounded bythree impermeable walls and one permeable wall. The printing parametersare also optimized to minimize the presence of defects.

[0097] A device that in final dimension is 1.5 cm×1.5 cm×3.5 cm andcontaining 200 μg of 17-DAN in a central core is fabricated. Thereleasing layer is composed of either PCL or PLLA printed with 20% oflow molecular weight PCL/chloroform. The non-releasing layer is composedof PLLA printed with 2.5% PCL/chloroform.

[0098] In one of the experiments, the permeable wall is replaced by animpermeable wall. The implant shows no drug release, clearlydemonstrating the ability to fabricate biodegradable surfaces that areimpervious.

[0099] In one of the experiments, the permeable wall is replaced by animpermeable wall. The implant shows no drug release, clearlydemonstrating the ability to fabricate biodegradable surfaces that areimpervious.

EXAMPLE 3

[0100] Fabrication of microdose oral dosage forms by conventional tabletpressing technique presents many content uniformity issues and safetyhazards. 3DP processing can be used to build highly accurate dosageforms by depositing metered amounts of medicaments(s) in the centerportion of the dosage form. Since the medicament can be completelyencapsulated therein, the content uniformity twill not be altered bysubsequent handling, packaging, or during storage. Furthermore, it willbe recognized that the safety hazards due to exposure to the medicamentbeing used to persons involved in the manufacture of the dosage formsare immediately reduced. The framework for micro-dosage tablets built by3DP further allows the release rate of the medicament from the centerportion to be controlled by the methods described herein and aspreviously set forth in U.S. Pat. No. 5,490,962.

[0101] In one particularly preferred embodiment, an oral dosage form ofthe present invention is constructed to release hormones in submilligramquantities. The combination of norethindrone acetate and ethinylestradiol is one such combination contemplated. The active component maybe 500 μg of norethindrone acetate and 2.5 μg of ethinyl estradiol. Thepowder material used may be selected from microcrystalline cellulose,lactose, arabinogalctans, starch, or super disintegrant. The bindersolution composition may contain arbinogalactans or Eudragits (e.g., amethacrylate). The architecture of the dosage form may be of singlechamber type or include multiple active chambers in order to effect thedesired release profile of both agents from the dosage form.

EXAMPLE 4

[0102] Materials

[0103] Sure-Jell® (Kraft General Foods, Inc., White Plains, N.Y., Lot6-032-P-0659-4, exp. February 1999) powder is used to build theframework for the microdose tablets (dosage forms). Fruit pectin is themajor ingredient of Sure-Jell. Fumaric acid is also present to assistgelling of the powder. As-received powder is fractionated by sievingthrough 100 mesh and 325 mesh screens to remove large agglomerates andfines. The tablets are built by using only the powder that is left onthe 325 mesh screen (d+45˜150 μm). Deionized water is used to bind theSure-Jell powder.

[0104] The active ingredient used in this set of microdose tablets is anantibacterial drug called nitroflirantoin (Sigma Specialty Chemicals,St. Louis, Mo., Lot 115H1012). An ethanolic (Aldrich, Milwaukee, Wis.,Lot 15013 HQ) solution of nitrofurantoin is deposited. The concentrationof the solution is 0.0188 mg/ml.

[0105] Fabrication

[0106] The 3DP parameters used to build the framework for microdosageforms are explained below. Sure-Jell powder is spread into 170 μm layersby manual spreading, using a stainless steel rod. The flow rate of thebinder, distilled water, is kept at 1.2 cc/min. Speed of the fast axisis 1.5 m/sec and each line is separated by 170 μm from the others. Aspring steel stencil (Rache Corp., Camarillo, Calif.) with an 11×11array of 1.04 cm circular openings is used to define the shape of thedosage forms. Ten 170 μm base layers are built with Sure-Jell and waterand active solution is deposited on the top surface of the tenth layer.

[0107] The flow rate of the nitrofurantoin solution is kept at 1.0cc/min and raster speed is kept at 1.6 m/sec. The active solution isdispensed throughout the entire surface of the tenth layer to achievethe dosage level of 1 μg per tablet. Total 5.32 μL of nitrofurantoinsolution is delivered per tablet. These parameters were calculated basedon the line spacing of 170 μm and the estimated total line segment of51.02 cm to cover the circular surface area of each dosage form.

[0108] After drying the active solution by waiting for 60 minutes,another 170 μm layer of Sure-Jell is spread on the top of the dosageforms and bound to the drug containing layer with distilled water. Thistop layer is designed to cover the active-containing region and preventthe loss of active ingredient during handling processes.

[0109] The tablets are allowed to air dry for 30 minutes, then thepowder bed is removed from TheriForm Alpha-0 machine and kept undervacuum (−760 mmHg) for 30 minutes to facilitate the removal of residualmoisture. Each dosage form is removed from the powder bed manually.

[0110] Analytical Methods

[0111] An ethanol extraction method is used to prepare the assay samplesfor UV-analysis (BioSpec1601, Shimadzu, Princeton, N.J.). Each tablet isground to powder form using an agate mortar and pestle. Caution is takennot to lose parts of the dosage form during the grinding process. Theground powder form of the tablet is transferred into vials. Five mlaliquots of ethanol are added to each vial using micro-pipettes(Eppendorf, Brinkmann Instruments, Westbury, N.Y.) and mixed for 15minutes on an orbital shaker (Environ Shaker, Lab-Line Instruments,Melrose Park, Ill.). Ethanol dissolves only two major ingredients of thedosage form: nitrofurantoin and fumaric acid. Nylon Acrodiscs (GelmanSciences, Ann Arbor, Mich.) were used to filter out particulates fromthe samples in order to minimize interference. UV-maximum fornitrofurantoin is at 356 nm while that of fumaric acid is around 270 nm.The UV-absorbance at 356 nm was taken to estimate the amount ofnitrofurantoin in each of the sample dosage forms. The assayconcentration of nitrofurantoin was in a well defined linear responseregion. A total of 18 tablets were tested for content uniformity.

[0112] Results

[0113] The UV-absorbance and corresponding nitrofurantoin content perindividual dosage form is summarized in Table 1. TABLE 1 ContentUniformity of Nitrofurantoin Microdosage Forms Sample UV- NitrofurantoinID absorbance per tablet (μg) 1 0.0112 0.936 2 0.0139 1.160 3 0.01421.190 4 0.0118 0.987 5 0.0129 1.078 6 0.0106 0.883 7 0.0131 1.099 80.0105 0.875 9 0.0096 0.804 10 0.0114 0.956 11 0.0111 0.926 12 0.01291.078 13 0.0118 0.987 14 0.0117 0.977 15 0.0140 1.170 16 0.0118 0.987 170.0120 1.007 18 0.0140 1.170

[0114] The lowest dose is 0.804 μg while the highest was 1.190 μg.Average of the 18 specimens was 1.01 μg per tablet with a standard,deviation of 0.113 μg (RSD=11.13%).

[0115] The above procedure demonstrates the ability to build dosageforms with very small amount of drug. Average content of 1.015 μg isonly 1% off from the intended dose. USP requirements for contentuniformity mandates that dosage units fall within the range of 85% to115% and the RSD less than or equal to 6.0%. The variability betweendosage forms can be reduced by fine tuning the process. FIG. 2(a)illustrate one embodiment which may be susceptible to edge losses. Minormodifications can be made to the tablet design so that theactive-containing region is less prone to edge losses during handling asshown in FIG. 2(b). An even more robust and safer architecture willencapsulate the active completely as shown in FIG. 2(c). Thisarchitecture has an advantage of eliminating the danger of exposing thehighly potent pharmaceutical agents to the hands of the workers andpatients, container walls, and neighboring tablets.

1. A method for forming a multiphasic dosage form containing at leasttwo pharmaceutically active materials comprising: preparing a firstlayer of pharmaceutically acceptable powder on a platform; forming afirst pattern of adhered particulates in the first layer by applying abinder to selected portions of the first layer wherein the pattern formsboundary walls within the layer; incorporating a first pharmaceuticallyactive material within a boundary formed in the first layer; preparing asecond layer of pharmaceutically acceptable particulates over the firstlayer; forming a second pattern of adhered particulates which is thesame or different from the first pattern by applying a binder toselected portions of the second layer, the second pattern being adheredto the first pattern along an interface thereof to thereby produce athree dimensional dosage form; and incorporating a secondpharmaceutically active material within a boundary formed in the secondlayer.
 2. A method as claimed in claim 1, wherein the steps of formingthe first and second patterns include forming first and second patternshaving different release profiles for the first and secondpharmaceutical materials.
 3. A method as claimed in claim 1, whereinpreparing the second layer of pharmaceutically acceptable particulatescomprises preparing a second layer having a different composition thanthe first layer of pharmaceutically acceptable particulates.
 4. A methodas claimed in claim 1, wherein applying a binder to selected portions ofthe second layer comprises applying a binder that is different than thebinder applied to the first layer.
 5. A method as claimed in claim 1,wherein the active ingredient is contained in the binder.
 6. A method asclaimed in claim 1, wherein the pharmaceutically active materials areapplied to the first and second layers with the respective binders.
 7. Amethod as claimed in claim 1, wherein the at least two pharmaceuticallyactive materials are incorporated into the first and second layersrespectively.
 8. A method as claimed in claim 1 further includingpreparing a third layer of pharmaceutically acceptable particulates overthe second layer and forming a third pattern of adhered particulateswhich is the same or different from the second pattern by applying abinder to selected portions of the thirds layers to produce a threedimensional dosage form of at least three layers.
 9. A method forforming a dosage form comprising the steps of: preparing a threedimensional pattern of a soluble material having a variable surfacetopography; spreading a layer of particulates over the soluble pattern,thereby partially filling in the variable surface topography; applyingbinder to the layer, thereby effecting adherence of adjacentparticulates of the layer; repeating, preparing a pattern, spreading alayer and applying a binder to form a three dimensional structurecomprising adhered particulates corresponding to the variable surfacetopography and the three dimensional pattern of soluble material; andremoving the soluble material by dissolution with a solvent in vitro orin vivo, thereby introducing at least one of a variable topography orchannels in the dosage form.
 10. A multiphasic dosage form comprising:an intraocular implant for delivery of at least two pharmaceuticallyactive materials comprising a first matrix of bound particulatesincorporating a first pharmaceutically active material and having afirst erosion or degradation rate for release of the first material, anda second matrix of bound particulates incorporating a secondpharmaceutically active material and having a second erosion ordegradation rate for release of the second material, the second erosionor degradation rate being different than the first erosion ordegradation rate.
 11. A multiphasic dosage form as claimed in claim 1,wherein the first pharmaceutically active material comprises 5-FU and isreleased in pulsatile form, and wherein the second pharmaceuticallyactive material is diclofenac and is released in continuous form.
 12. Amultiphasic dosage form for intraocular implant devices comprising: athree dimensional matrix including pharmaceutically acceptableparticulates adhered together, at least two pharmaceutically activematerials incorporated into the matrix wherein the firstpharmaceutically active material releases at a first rate and the secondpharmaceutically active material releases at a second rate.
 13. Theintraocular dosage form of claim 12 wherein the matrix has two differentthree dimensional architectures, the first internal architectureincluding walls, micro chambers and a top and bottom lids, the secondinternal architecture including a homogenous matrix.
 14. The intraoculardosage form of claim 12 wherein the walls are formed from chloroformcombined with PLGA.
 15. The intraocular dosage form of claim 12 whereinthe micro chamber lids are formed from P(FAD:SA)
 16. The intraoculardosage form of claim 12 wherein the first active ingredient is containedin the micro chamber.
 17. The intraocular dosage form of claim 12wherein the second active ingredient is contained in the homogenousmatrix.
 18. The intraocular dosage form of claim 12 wherein the firstactive ingredient is 5-FU and the second active ingredient isdiclofenac.